Chronotherapeutic strategy: Rhythm monitoring, manipulation and disruption

• Published in: Advanced drug delivery reviews 2010-07, Vol.62 (9), p.859-875
• Main Author: Ohdo, Shigehiro
• Format: Article
• Language: English
• Subjects: Allergic rhinitis; Animals; Biological clock; Chrono-DDS; Chronopharmacokinetics; Chronopharmacology; Chronotherapy; Circadian Clocks - physiology; Circadian rhythm; Circadian Rhythm Signaling Peptides and Proteins - metabolism; Drug Administration Schedule; Drug Chronotherapy; Drug Delivery Systems; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations - administration & dosage; Pharmaceutical Preparations - metabolism; Time Factors
• ISSN: 0169-409X; 1872-8294
• DOI: 10.1016/j.addr.2010.01.006

Mammalians circadian pacemaker resides in the paired suprachiasmatic nuclei (SCN) and influences a multitude of biological processes, including the sleep–wake rhythm. Clock genes are the genes that control the circadian rhythms in physiology and behavior. 24 h rhythm is demonstrated for the function of physiology and the pathophysiology of diseases. The effectiveness and toxicity of many drugs vary depending on dosing time. Such chronopharmacological phenomena are influenced by not only the pharmacodynamics but also pharmacokinetics of medications. The underlying mechanisms are associated with 24 h rhythms of biochemical, physiological and behavioral processes under the control of circadian clock. Thus, the knowledge of 24 h rhythm in the risk of disease plus evidence of 24 h rhythm dependencies of drug pharmacokinetics, effects, and safety constitutes the rationale for pharmacotherapy. Chronotherapy is especially relevant, when the risk and/or intensity of the symptoms of disease vary predictably over time as exemplified by allergic rhinitis, arthritis, asthma, myocardial infarction, congestive heart failure, stroke, and peptic ulcer disease. Morning once-daily administration of corticosteroid tablet medications results in little adrenocortical suppression, while the same daily dose split into four equal administrations to coincide with daily meals and bedtime results in significant hypothalamus–pituitary–adrenal (HPA) axis suppression. However, the drugs for several diseases are still given without regard to the time of day. Identification of a rhythmic marker for selecting dosing time will lead to improved progress and diffusion of chronopharmacotherapy. To monitor the rhythmic marker such as clock genes it may be useful to choose the most appropriate time of day for administration of drugs that may increase their therapeutic effects and/or reduce their side effects. Furthermore, to produce new rhythmicity by manipulating the conditions of living organs by using rhythmic administration of altered feeding schedules or several drugs appears to lead to the new concept of chronopharmacotherapy. Several drugs cause alterations in the 24 h rhythms of biochemical, physiological and behavioral processes. The alteration of rhythmicity is sometimes associated with therapeutic effects, or may lead to illness and altered homeostatic regulation. Attention should be paid to the alteration of biological clock and consider it an adverse effect, when it leads to altered